2. Academic Validation
  3. Disrupted betaine metabolism drives Th17 cell differentiation, mediating methamphetamine-induced depressive behaviors in male mice

Disrupted betaine metabolism drives Th17 cell differentiation, mediating methamphetamine-induced depressive behaviors in male mice

  • J Neuroinflammation. 2025 Aug 26;22(1):207. doi: 10.1186/s12974-025-03532-1.
Rongji Hui # 1 2,  Jiabao Xu # 1,  Hongchen Ma 1,  Tao Feng 1,  Congcong Hou 1,  Xintao Wang 1 3,  Mingyang Jin 1,  Feng Yu 1,  Yan Shi 4,  Bing Xie 1,  Ludi Zhang 1,  Bin Cong 5,  Chunling Ma 6 7,  Di Wen 8 9
Affiliations

Affiliations

  • 1 College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China.
  • 2 Hebei Medical University Basic Medicine Postdoctoral Research Station, Shijiazhuang, Hebei, 050017, P.R. China.
  • 3 Hebei Medical University Postdoctoral Research Station in Biology, Shijiazhuang, Hebei , 050017, P.R. China.
  • 4 Shanghai Key Laboratory of Forensic Medicine, Key Laboratory of Judicial Expertise, Department of Forensic Toxicology, Academy of Forensic Science, Shanghai Forensic Science Platform, Ministry of Justice, Shanghai, 200063, China.
  • 5 College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China. cong6406@hebmu.edu.cn.
  • 6 College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China. chunlingma@hebmu.edu.cn.
  • 7 Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei, 050017, P.R. China. chunlingma@hebmu.edu.cn.
  • 8 College of Forensic Medicine, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Hebei Medical University, Shijiazhuang, Hebei Province, 050017, China. wendi01125@hebmu.edu.cn.
  • 9 Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei, 050017, P.R. China. wendi01125@hebmu.edu.cn.
  • # Contributed equally.
PMID: 40859333 DOI: 10.1186/s12974-025-03532-1
Abstract

Methamphetamine (METH) abuse, a global public health concern, is closely linked to neuropsychiatric disorders such as depression. Although the central nervous system (CNS) damage induced by METH is well documented, the role of peripheral immune mechanisms remains underexplored. To investigate this, we establish a depressive-like mouse model in male mice using repeated intraperitoneal METH injections. Behavioral tests, flow cytometry, RNA Sequencing and metabolomics reveal the underlying mechanisms. METH exposure increases the differentiation of CD4⁺ T cells into Th17 cells in the spleen, likely driven by mitochondrial dysfunction and impaired betaine metabolism. These Th17 cells secrete elevated IL-17 A, which binds to IL-17RA on hippocampal CA1 neurons, activates the p38 MAPK signaling pathway, and disrupts synaptic plasticity. Interventions targeting Th17 cells or IL-17 A signaling significantly reduce depressive behavior. These findings uncover a novel peripheral immune mechanism in METH-related depression, wherein CD4⁺ T cell-derived IL-17 A contributes to hippocampal dysfunction via IL-17RA/p38 MAPK signaling. Targeting Th17 cells or IL-17 A may represent a promising therapeutic strategy for METH-associated neuropsychiatric disorders.

Supplementary Information: The online version contains supplementary material available at 10.1186/s12974-025-03532-1.

Keywords

Betaine metabolism; CD4⁺ T cells; Depressive behaviors; Methamphetamine; Synaptic plasticity; Th17 cells.

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